Memorial Sloan Kettering Cancer Center, New York, New York.
David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York.
Clin Adv Hematol Oncol. 2020 Mar;18(3):168-179.
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy that remains a challenge to treat. In pursuit of personalized medicine, researchers continue active exploration of the genetic and molecular framework of PDAC to apply novel therapeutics and enhance outcomes. In patients who have PDAC, germline mutations-such as those in the BRCA1/2 and PALB2 genes-are predominantly associated with the DNA damage response and repair pathway. On the basis of studies completed in patients with BRCA-mutated advanced breast and ovarian cancer, the poly(ADP-ribose) polymerase (PARP) inhibitors have been evaluated for safety, tolerability, and efficacy in patients with advanced PDAC who are carrying germline BRCA gene mutations. Results have demonstrated meaningful activity and identified BRCA as a predictive and targetable biomarker in PDAC, and have also identified the role of olaparib as a maintenance therapy in PDAC. On the basis of the principle of synthetic lethality, and to avert resistance to PARP inhibitors, clinical trials of combination therapy with PARP inhibitors and platinum-based chemotherapy have been conducted with an early signal. As we continue to explore the role of PARP inhibitors in the management of PDAC, recent clinical trials are studying the effectiveness of PARP inhibitors in combination with immunotherapy, targeted inhibitors, and angiogenesis inhibitors. The next steps are to understand the role of PARP inhibitors beyond germline BRCA in other homologous recombination repair gene mutations and in other subgroups of patients with PDAC.
胰腺导管腺癌 (PDAC) 是一种侵袭性恶性肿瘤，治疗仍然具有挑战性。为了追求个性化医疗，研究人员继续积极探索 PDAC 的遗传和分子框架，以应用新型疗法并改善治疗效果。在患有 PDAC 的患者中，种系突变，如 BRCA1/2 和 PALB2 基因中的突变，主要与 DNA 损伤反应和修复途径相关。基于在携带 BRCA 突变的晚期乳腺癌和卵巢癌患者中完成的研究，聚（ADP-核糖）聚合酶 (PARP) 抑制剂已在携带种系 BRCA 基因突变的晚期 PDAC 患者中进行了安全性、耐受性和疗效评估。结果表明该抑制剂具有显著的活性，并确定了 BRCA 作为 PDAC 的预测性和靶向性生物标志物，同时也确定了奥拉帕利在 PDAC 中的维持治疗作用。基于合成致死的原理，并为避免对 PARP 抑制剂的耐药性，已进行了 PARP 抑制剂与铂类化疗联合治疗的临床试验，早期结果显示出了积极的信号。随着我们继续探索 PARP 抑制剂在 PDAC 管理中的作用，最近的临床试验正在研究 PARP 抑制剂联合免疫疗法、靶向抑制剂和血管生成抑制剂的有效性。下一步是了解 PARP 抑制剂在其他同源重组修复基因突变和其他 PDAC 患者亚组中的作用。
